Professor Glenn Wilson, Gresham College, London

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THE BLACK DOG
THE PSYCHOLOGY OF DEPRESSSION

• Professor Glenn Wilson, Gresham College, London

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SYMPTOMS OF DEPRESSION

• .

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BIPOLAR MOOD DISORDER

• Unipolar depression is distinguished from
  bipolar mood disorder alternating periods of
  depression and mania. The manic phases include
  euphoria, impulsivity and flight of ideas.
  Depressive symptoms much the same as unipolar.
• Other variants are post-natal depression and
  seasonal affective disorder (winter depression).

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GENETIC INPUT

• Some 10 suffer major depression at some point
  in their lives.
• Twin studies suggest that 40-50 of the variance
  is genetic.
• Could mean that each case is half genetic and
  half environmental, or that some are entirely
  genetic and others not at all (Levinson
  Nichols, 2013).
• Having a depressed parent or sibling raises risk
  2/3x. If their depression is recurrent and of
  early origin, risk is elevated 4/5x.
• Overlap with bipolar disorder and anxiety (but
  also some separation).

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ORCHIDS vs DANDELIONS

• Gene/environment interactions in depression
  evoke comparison between orchids and dandelions
  (Dobbs 2013. Dandelions thrive in almost any
  environment Orchids do well in ideal conditions
  but wilt under bad.
• Depression-prone people genetically predisposed
  as sensitive to emotional knock-backs during
  development.
• Child abuse, neglect, unstable relationships and
  lack of social support in adulthood may all be
  implicated.

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LIFE STRESSES

• No one gene is responsible for depression (many
  involved).
• Certain gene locations have attracted particular
  research interest, e.g., the serotonin
  transporter gene 5-HTTLPR (or SERT). People with
  short versions of SERT more susceptible to life
  stresses, increasing vulnerability to depression
  (Caspi et al, 2010).

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WHAT IS STRESSFUL?

• Any change in our lives seems to be stressful,
  negative events slightly more so.
• Stressful events are related to the onset of
  major depression (Kendler et al, 1999). Mainly
  causal (misfortune) but about one-third down to
  depression-prone individuals making bad life
  choices (mismanagement).

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EMOTIONAL BRAIN CONNECTIVITY

• SERT effect is linked with an emotional
  processing circuit in the brain. The cingulate
  cortex and amygdala show less gray matter volume
  in short SERT carriers.
• Also less functional coupling between the two
  areas under fear stimulation, suggesting that
  amygdala response is poorly regulated in s-SERT
  people (rendering them more stress-prone).

Brain areas where s-SERT carriers have reduced
gray matter amygdala (L), Cingulate cortex (R).
(Pezawas et al, 2005)
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MONOAMINES

• Neurotransmitter activity is implicated in
  depression, esp. serotonin (modulates mood),
  nor-epinephrine (alertness) and dopamine
  (pleasure/reward).
• Organised as circuits running from brain stem
  and limbic regions to many cortical areas.
• Most anti-depressants amplify these
  monoamines. Effects of psychological therapies
  may also be observed in brain chemistry.

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SSRIs

• Selective serotonin reuptake inhibitors (e.g.,
  Prozac) work by blocking the reuptake of
  serotonin at the synapses, thus prolonging its
  positive effect on mood (contentment).
• Effect not immediate may take several weeks to
  work (if indeed they do).

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DO THE DRUGS WORK?

• Value of antidepressants much debated. They have
  side-effects and may be addictive.
• Not effective with mild depression placebos
  just as good (Fournier et al, 2010).
• At severe levels of depression on Hamilton
  Rating Scale, drugs outperform placebo but mainly
  because placebos are less effective (Kirsch et
  al, 2008).

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ST JOHNS WORT

• Extract of hypericum works as well as standard
  drugs for major depression. An SSRI with fewer
  side-effects? (Linde et al, 2009).
• Studies from German-speaking countries (where
  there is a long tradition of use) usually more
  positive.
• Drug companies little interested because herbs
  cannot be patented.
• Commercially available forms vary enormously
  probably not all effective.
• Being natural does not make them safe. Can
  interact with other drugs and cause
  photosensitivity.

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LEARNED HELPLESSNESS

• Seligman (1967) observed that dogs subjected to
  inescapable shock failed to take effective action
  when escape later became possible. Had learned to
  be helpless.
• Depression construed as a feeling of powerless
  (lack of control over events acquired from
  unhappy life experiences.
• Later recognised that causal attribution
  mediates effect. Pessimists tend to blame
  themselves rather than bad luck for negative
  outcomes, hence adopt submissive attitudes.

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THE VICIOUS CIRCLE

• Cognitive Behaviour Therapy based on premise
  that depression arises from negative,
  self-destructive thoughts. Low mood regarded as a
  consequence of maladaptive attitudes and beliefs.
• e.g., A person losing their job might say
  economic conditions are difficult, and look for
  a new job, or they could conclude I am a
  useless no one will ever employ me again.
• CBT aims to alter irrational and pessimistic
  thought patterns so that constructive action and
  improved mood will follow.

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HORSES FOR COURSES

• Patients with major depression are usually
  prescribed drugs but only 40 get better after
  2/3 months then another approach is tried. Would
  help to find a way of predicting response to
  treatment.
• Depressed patients with higher PET activity
  in the anterior insula did better with drugs (12
  weeks escitalopram) those with low AI activity
  responded to CBT but not drugs (McGrath et al,
  2013).
• Less intrusive ways to personalise treatment
  being sought, e.g., gene markers (Lester Eley,
  2013). People with short SERTs benefit more from
  CBT.

Anterior insula activity observed by PET-scan
(McGrath et al (2013).
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RECOVERY IN THE BRAIN

• Clinical improvement observed in PET-scans
  differs for drugs vs CBT.
• Recovery with paroxetine mostly seen as
  increases in prefrontal activity and decreases in
  hippocampus and cingulate.
• CBT improvement went with increased activity in
  the hippocampus and dorsal cingulate and
  decreases in frontal cortex.
• Difference bottom up chain of events vs
  top-down?
• (Goldapple et al, 2004).

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BRAIN REPAIR

• Once thought we are born with all the brain
  cells we ever have. Carbon-14 dating of
  hippocampal cells in deceased persons shows new
  cells are spawned in their lifetime. (Radioactive
  C-14 in atmosphere has declined since 1960s
  nuclear test ban).
• Clinical depression is associated with reduced
  neurogenesis in the hippocampus, apparently
  stress induced (since glucocorticoids are
  implicated). Failure of new cell growth may help
  account for low mood and memory impairment.
• Anti-depressant drugs promote neurogenesis
  (Anacker et al, 2011).

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LET THERE BE LIGHT

• Bright light alleviates depression, especially
  earlier dawn simulation for seasonal affective
  disorder (Golden al, 2005). Restoring blue
  wave-lengths missing in artificial light may be
  important.
• Effects as strong as Prozac but not additive if
  light therapy used as adjunct to medication.
• Apparently due to suppression of the release of
  melatonin, a sleep hormone that seems to be
  depressogenic.

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EXERCISE

• About as effective in treating depression as
  drugs and talk therapy (Rimer et al 2012
  Silveira et al, 2013) can be an adjunct to
  either. Long-term effects are questionable
  however (Krough et al, 2011).
• Benefits could be due to improved health,
  fitness, self-image, diversion of negative
  thoughts, exposure to fresh air/sunshine or
  social contact.
• Severe cases usually difficult to persuade to
  take exercise, so may be some circularity.

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PETS

• Animals provide companionship often missing in
  peoples lives (e.g., elderly, widowed, bullied
  children). Pets are non-judgemental make
  unconditional bonds. Their dependency adds
  purpose to life (child surrogates) and dogs need
  to be walked ( exercise).
• Many studies show benefits of animal contact in
  reducing stress and depression (self-report and
  physiological measures). Nepps et al (2011)
  animal-assisted therapy effects comparable to
  behavioural stress reduction programme.

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IN VINO FELICITAS

• Gea et al (2013) followed 5500 Spanish adults,
  aged 55-80, over 7 years. Moderate consumption of
  wine (2-7 glasses/week) went with 32 reduced
  risk of depression (although heavy drinking
  increased risk).
• Same factors which protect against
  cardiovascular disease (e.g., resveratrol) may
  prevent depression.
• Other possibilities Mediterranean diet
  (previous finding by same authors), general
  health, wealth, life-style social context of
  light drinking may mediate effect.

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A STIFF UPPER FACE

• Contriving facial expressions appropriate to
  particular emotions can induce the actual feeling
  of that emotion.
• By freezing the muscles needed to produce a
  frown, Botox may reduce symptoms of depression
  (Wollmer et al, 2012).
• Reverse likely to apply freezing laugh lines
  around eyes may obstruct happiness
• (Finzi, 2013).
• Danger that impairment of empathy could damage
  social relationships (appearance of
  insensitivity). Inability to express surprise
  could lead to gullibility?

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TRANSCRANIAL MAGNETIC STIMULATION

• Electromagnetic induction of weak currents in
  selected brain areas (esp. frontal) usually over
  several sessions.
• Non-invasive compared with ECT or surgery.
  Side-effects occasional seizures/headache.
• Some evidence for efficacy with depression but
  still largely experimental (Slotema et al, 2010).
  
• Mechanism unclear and many variables remain to
  be explored.
• Difficult to devise sham control to mimic
  sound/scalp sensations.

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RECREATIONAL DRUGS

• Not all environmental effects are psychological.
  MDMA (ecstasy), widely used in dance clubs,
  depletes the serotonin system in the brain,
  making the user more prone to depression. May be
  short-term (suicide Tuesday) or permanent.
• Briere et al (2012) adolescents use of ecstasy
  speed doubled subsequent depressive symptoms (5
  year follow-up).
• Previous users of ecstasy may be most at risk of
  depression (Roiser Sahakian, 2004).

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SPECIAL K

• Ketamine is another drug used for night-club
  highs/trances. Approved use as anaesthetic but
  current interest in possibilities as a
  fast-acting anti-depressant (Murrough et al,
  2013). SSRIs usually take weeks to work
  intravenous ketamine may lift depression in
  hours.
• Enhances glutamate transmission, raising neuron
  excitability. Parallel to effects of ECT and
  transcranial magnetic stimulation?
• Dangers include addiction, hallucination
  bladder damage but already used off-label in
  some US clinics for treatment-resistant
  depression (Stix, 2013).

Ketamine-induced increases in neural connectivity
observed in a rat brain (Ronald Duman, Yale Univ.)
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SUICIDE RISK

• Depression increases risk, esp. when severe and
  long-lasting (20x norm). Anorexia, drug use,
  chronic pain, PTSD, anxiety impulse-control
  disorders also raise risk.
• May be preceded by threats/jokes, tying up loose
  ends, sudden mood elevation.
• Risk factors family history, poor social
  support, availability of means.
• Women attempt 2x men (drug overdose) men
  succeed 2x women (firearms). LGBTs gt avge.
• Age lt14, and 65 have higher rates.
• Previous attempts esp. predictive when violent
  mode hanging, drowning, jumping, shooting
  (Runeson et al, 2010).
• Nightmares following a suicide attempt are a
  bad sign but not other sleep disturbances
  (Sjostrom, 2009).

Comedian Stephen Fry, who suffers from bipolar
disorder, has attempted suicide on more than one
occasion.
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COMPUTER TASKS

• Interviews re suicidal plans unreliable because
  patients conceal their intentions (78 deny
  intent just before killing themselves).
• Word associations and reaction times give
  subtler clues. Stroop and Implicit Associations
  tests used to measure attention to and ease of
  association between critical words Those with
  strong associations between self and
  death/suicide 6x more likely to attempt suicide
  within 6 mths (Nock, 2010).
• Better than known predictors (depression,
  history of suicide-attempts, own clinician
  expectations).

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BIOMARKERS

• A protein encoded by a gene on the X chromosome
  (SAT1) has recently been reported as a possible
  blood biomarker of suicide (Niculescu et al).
  This protein is associated with cellular damage
  and stress.
• Work so far has only involved small samples of
  men, mostly bipolar. If replicated, might have
  potential as test for suicide risk.

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ADAPTIVE VALUE?

• Women about 2x as susceptible to depression as
  men. Not just social factors depression in men
  goes with feminised finger ratios (Bailey Hurd,
  2005).
• Depression proneness may be price paid for
  greater emotional sensitivity (empathy and social
  communication skills).
• Similar selection might apply to s-SERT genes.
  Not eliminated over many thousands of years,
  hence likely to confer some advantage.
• Belsky et al (2009) people with s-SERT genes
  are susceptible to adversity but function better
  in supportive and enriching environments.
  Vulnerability better construed as plasticity?

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MEDICALISING MISERY

• Concern that anti-depressants are
  over-prescribed for mild depression.
• (1) Lack of resources for alternatives like talk
  therapy.
• (2) Fashionability among celebrities.
• (3) Commercial interests blur distinction
  between unhappiness and profound depression.
• There is an enormous amount of money to be made
  from prescribing marginally effective medications
  to large numbers of people (Wright, 2013).
• Danger of masking deprivation and social
  problems by medicalising them.

In certain Welsh valleys, where unemployment is
high, 1/6 adults are medicated thus qualifying
them for disability benefit.